NM_021116.4:c.1450-5G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021116.4(ADCY1):c.1450-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,326 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.012 ( 153 hom. )

Consequence

ADCY1
NM_021116.4 splice_region, intron

Scores

Splicing: ADA: 0.00003212

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.37

Publications

6 publications found

Variant links:

Genes affected

ADCY1 (HGNC:232): (adenylate cyclase 1) This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ADCY1 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
autosomal recessive nonsyndromic hearing loss 44
Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ADCY1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 7-45662054-G-T is Benign according to our data. Variant chr7-45662054-G-T is described in ClinVar as Benign. ClinVar VariationId is 517524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0121 (17612/1461070) while in subpopulation MID AF = 0.0222 (128/5758). AF 95% confidence interval is 0.0191. There are 153 homozygotes in GnomAdExome4. There are 8738 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ADCY1	NM_021116.4 link	c.1450-5G>T	splice_region_variant, intron_variant	Intron 7 of 19	ENST00000297323.12	NP_066939.1
ADCY1	NM_001281768.2 link	c.775-5G>T	splice_region_variant, intron_variant	Intron 8 of 9		NP_001268697.1
ADCY1	XM_005249584.4 link	c.1450-5G>T	splice_region_variant, intron_variant	Intron 7 of 18		XP_005249641.1
ADCY1	XM_005249585.3 link	c.1450-5G>T	splice_region_variant, intron_variant	Intron 7 of 8		XP_005249642.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ADCY1	ENST00000297323.12 link	c.1450-5G>T	splice_region_variant, intron_variant	Intron 7 of 19	1	NM_021116.4	ENSP00000297323.7
ADCY1	ENST00000432715.5 link	c.775-5G>T	splice_region_variant, intron_variant	Intron 8 of 9	2		ENSP00000392721.1
ADCY1	ENST00000621543.1 link	c.775-5G>T	splice_region_variant, intron_variant	Intron 7 of 8	5		ENSP00000479770.1
ADCY1	ENST00000646653.1 link	n.391-5G>T	splice_region_variant, intron_variant	Intron 3 of 7

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1747

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00719

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0501

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0126

AC:

3152

AN:

250766

AF XY:

0.0125

show subpopulations

Gnomad AFR exome

AF:

0.00868

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.0473

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0121

AC:

17612

AN:

1461070

Hom.:

153

Cov.:

AF XY:

0.0120

AC XY:

8738

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.00780

AC:

261

AN:

33468

American (AMR)

AF:

0.0105

AC:

467

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

1179

AN:

26096

East Asian (EAS)

AF:

0.000101

AC:

AN:

39688

South Asian (SAS)

AF:

0.00715

AC:

616

AN:

86106

European-Finnish (FIN)

AF:

0.0109

AC:

581

AN:

53410

Middle Eastern (MID)

AF:

0.0222

AC:

128

AN:

5758

European-Non Finnish (NFE)

AF:

0.0122

AC:

13513

AN:

1111502

Other (OTH)

AF:

0.0143

AC:

863

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

830

1660

2489

3319

4149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0115

AC:

1745

AN:

152256

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

882

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00715

AC:

297

AN:

41546

American (AMR)

AF:

0.0117

AC:

179

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0501

AC:

174

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00499

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0133

AC:

905

AN:

68020

Other (OTH)

AF:

0.0166

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

178

268

357

446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0115

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 10, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 05, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1450-5G>T in intron 7 of ADCY1: This variant is not expected to have clinical significance because it has been identified in 1.66% (1102/66292) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77524127).

ADCY1-related disorder

Benign:1

Jun 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.073

(source)

DANN

Benign

0.61

PhyloP100

-3.4

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over